Design, Synthesis, and Evaluation of Potent, Nonpeptidic Mimetics of Second Mitochondria-Derived Activator of Caspases

A series of new Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 10 binds to XIAP, cIAP-1, and cIAP-2 BIR3 proteins with K-i of 3.9, 0.37, and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC50 of 8.9 nM.